Cocrystal formation during cogrinding and storage is mediated by amorphous phase

Area of Science:

• Solid-state chemistry
• Pharmaceutical sciences
• Materials science

Background:

• Cocrystal formation is crucial for modifying drug properties.
• Understanding process-induced transformations is key for pharmaceutical manufacturing.
• The role of water and amorphous states in cocrystallization requires further investigation.

Purpose of the Study:

• To investigate the mechanisms of cocrystal formation during cogrinding and storage.
• To determine the effects of water on cocrystal formation using hydrated reactants and varying relative humidity (RH).
• To establish how process conditions influence solid-state transformations.

Main Methods:

• Utilized carbamazepine-saccharin (CBZ-SAC) as a model hydrogen-bonded cocrystal.
• Studied cogrinding under ambient and cryogenic conditions, using anhydrous, monohydrate, and dihydrate forms of carbamazepine (CBZ).
• Analyzed coground samples stored at 0% and 75% RH using X-ray powder diffraction (XRPD), Fourier-transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC).

Main Results:

• Cocrystals formed via cogrinding and storage mirrored those from solvent methods.
• Cogrinding hydrated CBZ and higher RH during storage accelerated cocrystallization rates.
• Cryogenic cogrinding induced greater amorphization than ambient cogrinding; the amorphous phase transformed into cocrystal during storage.

Conclusions:

• Amorphous phases generated during pharmaceutical processing promote cocrystal formation under conditions of increased molecular mobility.
• Water acts as a plasticizer, significantly enhancing the rate of cocrystallization.
• These findings provide critical insights for controlling process-induced solid-state transformations in pharmaceuticals.